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Chemotherapy and HAART to Treat AIDS-related Primary Brain Lymphoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00267865
Recruitment Status : Completed
First Posted : December 21, 2005
Results First Posted : May 1, 2020
Last Update Posted : June 1, 2020
Information provided by (Responsible Party):
Robert Yarchoan, National Cancer Institute (NCI)

Brief Summary:

This study will investigate the use of chemotherapy plus highly active antiretroviral therapy (HAART) in patients with Acquired Immunodeficiency Syndrome (AIDS)-related primary brain lymphoma. None of the drugs used in this study are experimental, but chemotherapy plus HAART has not been established as a standard treatment in patients with AIDS. The chemotherapy regimen used in this study (see below) was chosen because it may be less toxic to immune cells called T-lymphocytes than most drug treatments for lymphoma.

People with AIDS 18 and older and have primary brain lymphoma may be eligible for this study. Candidates are screened with a medical history and physical examination, magnetic resonance imaging (MRI), computed tomography (CT) and positron emission tomography (PET) scans, cerebrospinal fluid studies, brain biopsy at tumor sites, if possible, electrocardiogram and blood tests.

Participants undergo six 2-week "induction treatment" cycles of HAART plus chemotherapy with methotrexate, rituximab and leucovorin, followed by two 4-week "consolidation" treatment cycles using HAART, methotrexate and leucovorin, and then HAART alone. Rituximab is given by intravenous (intravenous (IV), through a vein) day 1 of each cycle. Also on day 1 IV fluids are given to lower acidity in the urine to protect the kidneys from the methotrexate. On day 2, methotrexate is infused through a vein over 4 hours. Starting 24 hours after initiation of the methotrexate infusion, leucovorin is given every 3 to 6 hours (first IV and then possibly by mouth) until the drug decreases to a target level in the blood. HAART is begun as soon as possible. The specific HAART regimen for each patient is determined individually. All patients are hospitalized the first week of every 2-week treatment cycle for safety monitoring. In addition to HAART and chemotherapy, patients undergo the following tests and procedures:

  • Intellectual functioning: Before starting treatment, patients are tested for their ability to understand basic concepts and coordination in order to be able to evaluate how the brain lymphoma affects thinking and concentration. After the lymphoma appears to have resolved, more formal and intensive tests are done. The intensive tests are repeated each year, and shorter, interim tests are done about every 6 months. Also, a specialist periodically monitors patients' understanding of HAART and the importance of this therapy.
  • Blood tests: Blood is drawn every day during hospitalizations to measure methotrexate levels and to evaluate kidney and liver function and blood counts. Blood is also drawn before starting therapy, when the lymphoma disappears, 6 months after completing treatment, and any time it appears that the lymphoma may have recurred to test for Epstein-Barr virus (EBV), a virus that is almost always present in AIDS-related primary brain lymphoma.
  • Imaging tests: Patients undergo magnetic resonance imaging (MRI) and positron emission tomography (PET) scans periodically to monitor the effects of treatment on the lymphoma. MRI scans are done after the 2nd, 4th, 6th, and 8th treatments, then every 2 months for three times, every 3 months for six times, every 6 months for four times, and then every year for 5 years, or sooner if there is a concern about the brain. PET scans are done after the first cycle, after the MRI suggests the lymphoma is gone, and then yearly.
  • Lumbar puncture (spinal tap): This test is done to look for EBV in the cerebrospinal fluid (CSF). Under local anesthetic, a needle is inserted in the space between the bones in the lower back where the CSF circulates below the spinal cord and a small amount of fluid is collected through the needle. This test is done at the same times as the blood tests for EBV.
  • Eye examinations: Patients' eyes are examined periodically because brain lymphoma can sometimes spread to the eye and because some people with AIDS-related primary brain lymphoma are at risk of certain eye infections.

Condition or disease Intervention/treatment Phase
AIDS-Related-Primary Central Nervous System Lymphoma Drug: Methotrexate Drug: Rituximab Drug: Leucovorin Phase 2

Detailed Description:

Background: Acquired Immunodeficiency Syndrome (AIDS)-related primary central nervous system lymphoma (AR-PCNSL) is an Epstein-Barr virus (EBV)-driven lymphoproliferative process that typically results in death within a few months. Essentially all of the cases are immunoblastic cluster of differentiation 20 (CD20+) tumors, and occur once the cluster of differentiation 4 (CD4+) cells have fallen to below 50 cells/mm^3. Highly active antiretroviral therapy (HAART) can result in immune reconstitution that decreases the risk of AR-PCNSL. However, a subset of human immunodeficiency virus (HIV)-infected patients still develops ARPCNSL, often because they are unaware that they are HIV infected, or they do not take HAART. Treatment options for such patients are limited. In the non-AIDS setting, chemotherapy has become the standard of care for primary central nervous system lymphoma (PCNSL) and late neurocognitive decline consequent to radiotherapy can be avoided by such approaches. In the pre-HAART era, AR-PCNSL was generally treated with whole brain radiotherapy, however death due to recurrent lymphoma or to other AIDS complications occurred prior to the potential manifestations of late occurring radiation-related neurotoxicity. Radiation-sparing approaches have not been studied in AR-PCNSL in the HAART era, where advances in antiretroviral therapy have made curative intent chemotherapy feasible for most patients with HIV infection.

Objectives: The primary objective of this study is to estimate the fraction of patients with AR-PCNSL receiving experimental treatment consisting of HAART, combined with rituximab, high-dose methotrexate and leucovorin (R-HD-MTX) who are alive and without recurrent lymphoma or severe cognitive problems at two years. .

Eligibility: HIV-infected, age 18 years or older, AR-PCSNL that has not previously been treated, and be able to give informed consent or have a durable power of attorney who can provide informed consent, HIV profile that makes them likely to respond to HAART. There are a number of other specific inclusion and exclusion criteria, in part to exclude patients who would be unlikely to tolerate the therapy.

Design: Phase II pilot study investigating R-HD-MTX given with leucovorin rescue and HAART as a treatment for AR-PCNSL. Evaluation will include quantitative measurement of lymphocyte subsets, quantitative polymerase chain reaction (PCR) of HIV and EBV viral loads (including both blood and cerebrospinal fluid in the case of EBV) to assess immune response and anti-viral effects. Tumor evaluation with brain magnetic resonance imaging (MRI) and brain fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET scans) will be used for staging and response assessment. Longitudinal neuropsychologic testing after complete responses are documented will serve to evaluate neurocognitive parameters post therapy.

a separate cohort for additional secondary endpoints.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: AIDS-Related Primary Central Nervous System Lymphoma: A Phase II Pilot Study of High-Dose Intravenous Methotrexate With Rituximab Leucovorin Rescue and Highly Active Antiretroviral Therapy
Actual Study Start Date : September 14, 2006
Actual Primary Completion Date : September 18, 2019
Actual Study Completion Date : September 19, 2019

Arm Intervention/treatment
Experimental: Rituximab, High-Dose Methotrexate & Leucovorin Treatment
Induction treatment cycles with rituximab, high-dose methotrexate and leucovorin will be administered every 2 weeks for 6 cycles. Two additional consolidation cycles of high-dose methotrexate without rituximab will be administered at 4 weeks and 8 weeks following completion of the combined therapy.
Drug: Methotrexate
6000 mg/m^2 will be administered by intravenous infusion over 4 hours after confirming that the recipient patients urine pH is within the range greater than or equal to 7 to less than or equal to 8, and urine output is greater than or equal to 100 mL/hour.
Other Names:
  • Xatmep
  • Trexall
  • Otrexup (PF)
  • Rasuvo

Drug: Rituximab
375 mg/m^2 intravenous (IV) day 1 of each cycle prior to administration of high-dose methotrexate
Other Names:
  • Rituxan
  • MabThera

Drug: Leucovorin
Leucovorin calcium doses will be administered orally or by short intravenous (IV) infusion over 15 minutes
Other Names:
  • Folinic acid
  • citrovorum factor

Primary Outcome Measures :
  1. Number of Patients Alive at 2 Years Without Recurrent Brain Lymphoma or Severe Neurocognitive Defects [ Time Frame: 2 years ]
    Recurrent lymphoma as defined by the International Primary Central Nervous System (CNS) Lymphoma Collaborative Group for response assessment of aggressive Non-Hodgkin's Lymphoma (NHL) using fluorodeoxyglucose F 18 (18FDG-PET). Severe cognitive problems are defined as the inability to carry out normal activities with minimal difficulty and not requiring nursing care or hospitalization because of neurological impairment.

Secondary Outcome Measures :
  1. Number of Participants With Serious and Non-serious Adverse Events [ Time Frame: Date treatment consent signed to date off study, approximately 142 months and 11 days. ]
    Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

  2. Number of Participants With Response to Treatment After Rituximab, High-Dose Methotrexate (R-HD-MTX) Induction [ Time Frame: At the end of 6 cycles or 12 weeks of treatment ]
    Response was assessed by the International Workshop Criteria for Non-Hodgkin's Lymphoma. Complete Response is disappearance of all enhancing lesions on magnetic resonance imaging of the brain. Partial Response is a reduction of enhancing tumor volume by more than 50% for at least 4 weeks. Progressive Disease is an increase of tumor volume of more than 25% or occurrence of new lesions.

  3. Estimated Percentage of Participants Overall Survival [ Time Frame: Time from treatment start date until date of death or date last known alive, approximately 60 months ]
    Participants that are estimated to be alive or last known to be alive after Rituximab, High-Dose Methotrexate and Leucovorin treatment.

  4. Median Mini Mental Status Exam (MMSE) Score in Surviving Participants After Rituximab, High-Dose Methotrexate & Leucovorin ( R-HD-MTX) Treatment [ Time Frame: up to 2.5 years ]
    The MMSE is scored out of a maximum of 30 points. A score of >25 is considered normal, with scores <25 indicating different levels of cognitive impairment: mild (21-24) moderate (10-20), and severe (0-10).

  5. Change From Baseline in Cluster of Differentiation 4 (CD4) T Cell Count at up to 2.5 Years [ Time Frame: Baseline and up to 2.5 years ]
    An increase in CD4 cells is determined by the number of CD4+ T lymphocytes /µL of peripheral blood.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Positive human immunodeficiency virus (HIV) serology (previous records acceptable)

  • Diagnosis of Primary Central Nervous System Lymphoma
  • Confirmed histopathologic diagnosis by National Cancer Institute (NCI) Laboratory of Pathology
  • If tissue diagnosis is not feasible for any reason, such as undue risk to the patient to acquire tissue diagnosis, the following will be accepted as confirmed Acquired immunodeficiency syndrome-related primary central nervous system lymphoma (AR-PCNSL) diagnosis:
  • Positive brain fluro-2-deoxy-d-glucose positron emission tomography (FDG-PET) and
  • Epstein Barr Virus (EBV) detected in the cerebrospinal fluid (CSF) using polymerase chain reaction (PCR)
  • Age 18 years or greater
  • Eastern Cooperative Oncology Group (ECOG) performance less than or equal to 0-4
  • Ability to understand and willing to provide informed consent
  • If patient unable to understand informed consent, a previously designated durable power of attorney for healthcare or an individual with legal authority may substitute in this capacity
  • Assignment of a durable power of attorney for healthcare if not already done


  • Prior therapy for central nervous system (CNS) lymphoma
  • Steroids not an exclusion
  • Evidence of lymphoma outside of the central nervous system
  • Ocular involvement will not exclude
  • Multidrug resistant HIV not amenable to long-term suppression based on either or both:
  • Clinical history of poor adherence to multiple antiretroviral drugs deemed sufficient to render effective HIV control unattainable;
  • HIV mutational analysis (genotyping and/or phenotyping) that reveals high-level resistance to more than 1 class of anti-HIV drugs such that a combination regimen comprised of agents from at least two drug classes can not be devised to suppress HIV long-term.
  • Refusal to adhere to highly active antiretroviral therapy (HAART)
  • Concurrent malignancy other than Kaposi sarcoma, resectable squamous cell or basal cell skin cancer, or T1 anal cancer amenable to surgical resection.
  • Heart failure, Class IV by New York Heart Association criteria
  • Chronic Liver Disease, Child-Pugh class B or C


  • Refusal to practice contraception during chemotherapy.
  • Any condition or set of circumstances that the Principal Investigator or Protocol Chair interprets as creating undue risk to the patient by participating on this study or would make the patient unlikely to comply with the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00267865

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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Robert Yarchoan, M.D. National Cancer Institute (NCI)
  Study Documents (Full-Text)

Documents provided by Robert Yarchoan, National Cancer Institute (NCI):
Informed Consent Form  [PDF] March 17, 2018

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Robert Yarchoan, Principal Investigator, National Cancer Institute (NCI) Identifier: NCT00267865    
Obsolete Identifiers: NCT00304044
Other Study ID Numbers: 060051
First Posted: December 21, 2005    Key Record Dates
Results First Posted: May 1, 2020
Last Update Posted: June 1, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Robert Yarchoan, National Cancer Institute (NCI):
Human immunodeficiency virus
Acquired immunodeficiency syndrome
High Dose Methotrexate
CNS Lymphoma
Central Nervous System Lymphoma
Epstein-Barr virus
Additional relevant MeSH terms:
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Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Nucleic Acid Synthesis Inhibitors
Protective Agents
Vitamin B Complex